Abstract 4520: Inhibition of melanoma growth by small molecules that attenuate PI3K/PDK1 signaling and promote ATF2 mitochondrial localization

Abstract

Abstract Phosphoinositide-dependent kinase-1 (PDK-1) phosphorylates members of the AGC kinase superfamily, including AKT and PKC. We recently demonstrated the importance of PDK1 in melanoma development and progression (Oncogene 2013). Genetic ablation of PDK1 in melanocytes effectively delayed melanoma development and inhibited metastasis in a Braf/Cdkn2a model with WT or mutant Pten. In an effort to identify small molecule inhibitors that could affect the PDK1 signaling we characterized SBI-0089410, a small molecule identified in a screen for nuclear exclusion of the transcription factor ATF2, which attenuates its oncogenic activity while enabling its function at the mitochondrial membrane to promote apoptosis. SBI-0089410 reduced melanoma cell viability, inhibited colony formation and spheroid growth, decreased mitochondrial membrane permeability, decreased ATF2 phosphorylation by PKCϵ and altered ATF2 transcriptional activity. Notably, the effect of SBI-0089401 was attenuated by the overexpression of constitutively active PKCϵ or ATF2T52E, which carries a phosphomimetic mutation at the PKCϵ phosphorylation site. Reverse phase protein array (RPPA), validated by western blot analysis, revealed that SBI-408910 attenuates PI3K/AKT/PDK1 signaling pathways. In vivo, SBI-089410 attenuated the growth of Braf/Cdkn2a/Pten tumors in a syngeneic B6 mouse model, as well as prevented their resistance to BRAFi. Our studies substantiate the importance of targeting PI3K/PDK1 signaling in melanoma as a means for effective therapy and prevention of chemoresistance. Citation Format: Tal Varsano, Yongmei Feng, Giuseppina Claps, Marzia Scortegagna, Eric Lau, Marilyn Leonard, Anthony Pinkerton, Maurizio Pellecchia, Michael Davies, Marcus Bosenberg, Ze'ev Ronai. Inhibition of melanoma growth by small molecules that attenuate PI3K/PDK1 signaling and promote ATF2 mitochondrial localization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4520. doi:10.1158/1538-7445.AM2014-4520